LA JOLLA, CALIF., March 15, 2004 -- Researchers at The Burnham
Insititute have found that orlistat (brand name, Xenical), commonly prescribed
as an anti-obesity drug, has a positive side-effect: it inhibits
cancer growth.

Team leader Dr. Jeffrey Smith made this discovery using an
activity-based proteomics screening technique developed in his
laboratory that makes it possible to identify active targets and
simultaneously screen for their inhibitors. These results were to
be published in the journal Cancer Research on March 15.

The metabolism of a tumor cell is different from its normal
counterpart cell. Scientists have long suspected that metabolism is
connected to tumor progression. Dr. Smith and co-workers designed a
proteomics screen based on monitoring the activity of a family of
enzymes--serine hydrolyases--involved in metabolism. They used
their screen to compare normal prostate cells with prostate cancer
cells and discovered that the prostate cancer cells are affected by
an increased activity of fatty acid synthase. Fatty acid synthase
is the enzyme that converts dietary carbohydrate to fat.

The screen also identified orlistat as an inhibitor of fatty
acid synthase.

These discoveries, made in vitro, held true when tested in mice.
When they administered orlistat to mice bearing prostate tumors,
the Smith laboratory team discovered that the drug was able to
inhibit tumor growth in mice. Further experiments confirmed that
orlistat has no effect on normal prostate cells and no apparent
side effects in the mice; it acts specifically as fatty acid
synthase.

Additional screening of breast cancer and colon cancer cells
revealed that fatty acid synthase activity is also upregulated in
these tumors, presenting the possibility of designing new
treatments for these cancers based on inhibiting the enzyme's
activity with orlistat or a new drug based on orlistat's inhibitory
activity.

Orlistat was originally developed as an inhibitor of pancreatic
lipase. Pancreatic lipase is a member of the same enzyme family --
the serine hyrdolases -- used in Smith's screening. It is involved
in processing of fats in the digestive tract, which is how the drug
prevents adsorption of dietary fat.

The method developed by Dr. Smith represents a quantum leap in
drug discovery. So-called "activity-based" proteomics screening is
a new frontier in medical research, based on applying information
gleaned from the human genome project. The ability to compile a
comprehensive profile of a potential drug's activities, revealing
unintended activities along with the intended behaviors targeted by
the drug offers a systematic way to simulate how a drug will work,
before it is actually tested in animals and humans.

Given the time and cost inherent in developing new treatments,
activity-based proteomics screening opens up a new route for
finding effective treatments based on monitoring basic cell
behaviors, such as metabolism or respiration.

Proteomics screening is an efficient way to determine proof of
concept needed before a potential treatment can be refined for
clinical trials: in a matter of weeks, Dr. Smith was able to glean
the initial discovery that linked excessive fatty acid synthase
activity with flawed metabolism in cancer cells, and identified
orlistat as its inhibitor.

"This discovery with orlistat has given us a very nice wedge
with which we can go in and perturb tumor cells and ask the
question, 'What are the active targets, what are the other changes
that take place when you inhibit fatty acid synthase?'", says Dr.
Smith, "and that will give us really good insights into the
mechanism, and we anticipate that's going to reveal a whole swath
of additional drug targets along this pathway. This is a big
advance in the sense that we have an approved drug -- approved for
one indication -- that has another target and another potential
disease indication, prostate cancer."

Dr. Smith is Associate Scientific Director for Technology at The
Burnham Institute, where he is also a Associate Professor in the
Institute's NCI-designated Cancer Center. Co-authors contributing
to this study include Drs. Steven J. Kridel and Fumiko Axelrod,
postdoctoral fellows at The Burnham Institute, and Dr. Natasha
Rozenkrantz of Activix Biosciences in La Jolla.

This research was supported by grants from the National Cancer
Institute, and the Department of Defense's Prostate Cancer Program.
The Burnham Institute is an independent, nonprofit, public benefit
organization dedicated to basic biomedical research principally in
the areas of cancer, aging, and the neurosciences.